Clinical Trials List
Protocol NumberCLDK378A2301
NCT Number(ClinicalTrials.gov Identfier)NCT01828099
2013-07-09 - 2024-01-07
Phase III
Terminated7
ICD-10C34.90
Malignant neoplasm of unspecified part of unspecified bronchus or lung
ICD-10C34.91
Malignant neoplasm of unspecified part of right bronchus or lung
ICD-10C34.92
Malignant neoplasm of unspecified part of left bronchus or lung
ICD-10C7A.090
Malignant carcinoid tumor of the bronchus and lung
ICD-10Z51.12
Encounter for antineoplastic immunotherapy
ICD-9162.9
Malignant neoplasm of bronchus and lung, unspecified
A phase III multicenter, randomized study of oral LDK378 versus standard chemotherapy in previously untreated adult patients with ALK rearranged (ALK-positive), stage IIIB or IV, non-squamous non-small cell lung cancer
-
Trial Applicant
NOVARTIS (TAIWAN) CO., LTD.
-
Sponsor
Novartis Pharmaceuticals
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Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- 蔡俊明 Division of Thoracic Medicine
- Chao-Hua Chiu Division of Thoracic Medicine
- Chi-Lu Chiang 未分科
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Chih-Hung Chen Division of Thoracic Medicine
- 吳振德 Division of Radiology
- Chien-Ying Liu Division of Thoracic Medicine
- Wen-Cheng Chang Division of Hematology & Oncology
- Chih-Liang Wang Division of Thoracic Medicine
- Chih-Hung Chen Division of Thoracic Medicine
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- KUO-HSUAN HSU Division of Thoracic Medicine
- 陳焜結 Division of Thoracic Medicine
- JENG-SEN TSENG Division of Thoracic Medicine
- Gee-chen Chang Division of Thoracic Medicine
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Yu-Min Yeh Division of Hematology & Oncology
- Wei-Pang Chung 無
- Wen-Pin Su Division of Hematology & Oncology
- Shang-Yin Wu Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- 王逸熙 Division of Thoracic Medicine
- Chia-Cheng Tseng Division of Thoracic Medicine
- CHIN-CHOU WANG Division of Thoracic Medicine
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Chih-Yen Tu Division of Thoracic Medicine
- Wei-Chun Chen Division of Thoracic Medicine
- Chen Chia-Hung Division of Thoracic Medicine
- 陳鴻仁 Division of Thoracic Medicine
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- James Chih-Hsin Yang Division of Hematology & Oncology
- CHAO-CHI HO CHAO-CHI HO Division of General Internal Medicine
- 蔡子修 Division of General Internal Medicine
- Chia-Chi Lin Division of Hematology & Oncology
- 林育麟 Division of Hematology & Oncology
- JIN-YUAN SHIH Division of General Internal Medicine
- 廖唯昱 Division of General Internal Medicine
- 陳冠宇 Division of General Internal Medicine
- Jih-Hsiang Lee Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Condition/Disease
Non small cell lung cancer
Objectives
To compare the efficacy and safety of LDK378 with standard first-line chemotherapy (pemetrexed plus cisplatin or carboplatin) in patients with stage IIIB or IV, non-squamous NSCLC harboring a confirmed ALK rearrangement, using the Ventana immunohistochemistry (IHC) test.
Primary Objective(s) and Key Secondary Objective
The primary objective is to compare the antitumor activity of LDK378 versus reference chemotherapy, as measured by progression free survival (PFS) determined by a Blinded Independent Review Committee (BIRC).
The key secondary objective is to compare overall survival in patients treated with LDK378 versus reference chemotherapy
Secondary Objectives
- To assess the antitumor activity of LDK378 versus reference chemotherapy, as measured by overall response rate (ORR), duration of response (DOR), disease control rate (DCR), and time to response (TTR) determined by BIRC and by investigators.
- To assess the antitumor activity of LDK378 versus reference chemotherapy, as measured by PFS determined by investigators.
- To evaluate the safety profile of LDK378 versus reference chemotherapy.
- To assess the effect of LDK378 versus reference chemotherapy on patient reported outcomes (PRO), including disease related symptoms, functioning, and health-related quality of life.
- To characterize the PK of LDK378 in this patient population.
Test Drug
LDK378
Active Ingredient
LDK378
Dosage Form
capsule
Dosage
150
Endpoints
Efficacy assessments
Tumor assessment by RECIST 1.1 as evaluated by BIRC and by investigator.
Safety assessments
Adverse Events (AEs) including:
- Serious AEs (SAEs)
- Laboratory profiles
-- hematology
-- biochemistry
-- urinalysis
-- coagulation
-- pregnancy test (females)
-- hormones (males only)
- Physical examination
- Vital signs
- Electrocardiograms (ECG)
- WHO performance status
Other assessments
- Patient scores on the EORTC QLQ-C30/LC13, LCSS, and EQ-5D questionnaires
- Trough and extensive PK
- Extensive ECG and Blood Pressure
- Exploratory biomarkers
Tumor assessment by RECIST 1.1 as evaluated by BIRC and by investigator.
Safety assessments
Adverse Events (AEs) including:
- Serious AEs (SAEs)
- Laboratory profiles
-- hematology
-- biochemistry
-- urinalysis
-- coagulation
-- pregnancy test (females)
-- hormones (males only)
- Physical examination
- Vital signs
- Electrocardiograms (ECG)
- WHO performance status
Other assessments
- Patient scores on the EORTC QLQ-C30/LC13, LCSS, and EQ-5D questionnaires
- Trough and extensive PK
- Extensive ECG and Blood Pressure
- Exploratory biomarkers
Inclution Criteria
Inclusion criteria
1. Patient has a histologically or cytologically confirmed diagnosis of non-squamous
NSCLC that is ALK positive as assessed by the Ventana IHC test. The test will be
performed at Novartis designated central laboratories.
2. . Patient has newly diagnosed stage IIIB or IV NSCLC or relapsed locally advanced or
metastatic NSCLC not previously treated with any systemic anti-cancer therapy (e.g.
cytotoxic drugs, monoclonal antibody therapy, crizotinib or other ALK inhibitors, or other
targeted therapies, either experimental or not), with exception of neo-adjuvant or adjuvant
therapy as depicted in criterion 6. (For AJCC stage groupings and TNM definitions, refer
to NCI 2012 guidelines)
3. Patient has at least one measurable lesion as defined by RECIST 1.1. A previously irradiated site lesion may only be counted as a target lesion if there is clear sign of
progression since the irradiation.
4. Patient with clinically and neurologically stable central nervous system (CNS) metastases
who have not required increasing doses of steroids within the 2 weeks prior to screening to
manage CNS symptoms.
5. Patient is 18 years of age or older at the time of informed consent.
6. Patient who received previous neo-adjuvant or adjuvant systemic therapy will be eligible
for enrollment only if relapse has occurred more than 12 months from the end of the neoadjuvant or adjuvant systemic therapy. Patients must have recovered from all toxicities
related to prior (neo-) adjuvant systemic therapy to grade ≤ 1 (CTCAE v 4.03). Exception
to this criterion: patients with any grade of alopecia are allowed to enter the study.
7. Patient must meet the following laboratory values at the screening visit:
WBC count ≥ 4.0 x 109 /L
Absolute Neutrophil Count ≥ 1.5 x 109/L
Platelets ≥ 100 x 109/L
Hemoglobin (Hgb) ≥ 9 g/dL
Serum creatinine < 1.5 mg/dL and /or calculated creatinine clearance (using Cockcroft-Gault formula) ≥ 50 mL/min
Total bilirubin < 1.5 x ULN except for patients with Gilbert’s syndrome who may only be included if total bilirubin < 3.0 x ULN or direct bilirubin < 1.5 x ULN
Aspartate transaminase (AST) < 2.5 x ULN, except for patients with liver metastasis, who are only included if AST < 5 x ULN
Alanine transaminase (ALT) < 2.5 x ULN, except for patients with liver metastasis, who are only included if ALT < 5 x ULN
Alkaline phosphatase (ALP) < 5.0 x ULN
8. Patient must have the following laboratory values ≥ lower limit of normal (LLN) or corrected to within normal limits with supplements during screening:
Potassium ≥ LLN
Magnesium ≥ LLN
Phosphorus ≥ LLN
Total calcium (corrected for serum albumin) ≥LLN
9. Patient has life expectancy ≥ 12 weeks.
10. Patient has a WHO performance status 0-2.
11. Patient has the ability to understand and provide signed informed consent.
1. Patient has a histologically or cytologically confirmed diagnosis of non-squamous
NSCLC that is ALK positive as assessed by the Ventana IHC test. The test will be
performed at Novartis designated central laboratories.
2. . Patient has newly diagnosed stage IIIB or IV NSCLC or relapsed locally advanced or
metastatic NSCLC not previously treated with any systemic anti-cancer therapy (e.g.
cytotoxic drugs, monoclonal antibody therapy, crizotinib or other ALK inhibitors, or other
targeted therapies, either experimental or not), with exception of neo-adjuvant or adjuvant
therapy as depicted in criterion 6. (For AJCC stage groupings and TNM definitions, refer
to NCI 2012 guidelines)
3. Patient has at least one measurable lesion as defined by RECIST 1.1. A previously irradiated site lesion may only be counted as a target lesion if there is clear sign of
progression since the irradiation.
4. Patient with clinically and neurologically stable central nervous system (CNS) metastases
who have not required increasing doses of steroids within the 2 weeks prior to screening to
manage CNS symptoms.
5. Patient is 18 years of age or older at the time of informed consent.
6. Patient who received previous neo-adjuvant or adjuvant systemic therapy will be eligible
for enrollment only if relapse has occurred more than 12 months from the end of the neoadjuvant or adjuvant systemic therapy. Patients must have recovered from all toxicities
related to prior (neo-) adjuvant systemic therapy to grade ≤ 1 (CTCAE v 4.03). Exception
to this criterion: patients with any grade of alopecia are allowed to enter the study.
7. Patient must meet the following laboratory values at the screening visit:
WBC count ≥ 4.0 x 109 /L
Absolute Neutrophil Count ≥ 1.5 x 109/L
Platelets ≥ 100 x 109/L
Hemoglobin (Hgb) ≥ 9 g/dL
Serum creatinine < 1.5 mg/dL and /or calculated creatinine clearance (using Cockcroft-Gault formula) ≥ 50 mL/min
Total bilirubin < 1.5 x ULN except for patients with Gilbert’s syndrome who may only be included if total bilirubin < 3.0 x ULN or direct bilirubin < 1.5 x ULN
Aspartate transaminase (AST) < 2.5 x ULN, except for patients with liver metastasis, who are only included if AST < 5 x ULN
Alanine transaminase (ALT) < 2.5 x ULN, except for patients with liver metastasis, who are only included if ALT < 5 x ULN
Alkaline phosphatase (ALP) < 5.0 x ULN
8. Patient must have the following laboratory values ≥ lower limit of normal (LLN) or corrected to within normal limits with supplements during screening:
Potassium ≥ LLN
Magnesium ≥ LLN
Phosphorus ≥ LLN
Total calcium (corrected for serum albumin) ≥LLN
9. Patient has life expectancy ≥ 12 weeks.
10. Patient has a WHO performance status 0-2.
11. Patient has the ability to understand and provide signed informed consent.
Exclusion Criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patient with known hypersensitivity to any of the excipients of LDK378 (microcrystalline
cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate)
2. Patient with a history of severe hypersensitivity reaction to platinum containing drugs,
pemetrexed or any known excipients of these drugs.
3. Patient has received previous systemic anticancer therapy (e.g. cytotoxic drugs, monoclonal antibody therapy, crizotinib or other ALK inhibitors, or other targeted therapies, either experimental or not) for newly diagnosed stage IIIB or IV NSCLC or relapsed locally advanced or metastatic NSCLC with exception of neo-adjuvant or adjuvant therapy as depicted in inclusion criteria 6.
4. Patient with symptomatic CNS metastases who is neurologically unstable or has required
increasing doses of steroids within the 2 weeks prior to screening to manage CNS symptoms.
5. Patient has history of carcinomatous meningitis
6. Patient has received radiotherapy ≤ 2 weeks prior to starting the study treatment or has not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study treatment is allowed.
7.Patient has had major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within
4 weeks prior (2 weeks for resection of brain metastases) to starting study treatment or has
not recovered from side effects of such procedure. Video-assisted thoracic surgery (VATS) and mediastinoscopy will not be counted as major surgery and patients can receive study treatment ≥1 week after the procedure.
8. Patient with a concurrent malignancy or history of a malignant disease other than NSCLC
that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this
exclusion include the following: completely resected basal cell and squamous cell skin
cancers, and completely resected carcinoma in situ of any type.
9. Patient has clinically significant, uncontrolled heart disease and/or recent cardiac event
(within 6 months), such as:
Unstable angina within 6 months prior to screening
Myocardial infarction within 6 months prior to screening
History of documented congestive heart failure (New York Heart Association functional classification III-IV)
Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without antihypertensive medication. Initiation or adjustment of antihypertensive medication (s) is allowed prior to screening .
Ventricular arrhythmias.
Supraventricular and nodal arrhythmias not controlled with medication.
Other cardiac arrhythmia not controlled with medication.
Corrected QT (QTcF) > 470 ms using Fridericia’s correction on the screening ECG (as mean of triplicate ECGs)
10. Patient has impairment of GI function or GI disease that may significantly alter the
absorption of LDK378 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea,
or malabsorption syndrome).
11. Patient receiving treatment with medications that meet one of the following criteria and
that cannot be discontinued at least 1 week prior to the start of treatment with LDK378
and for the duration of the study:
Strong inhibitors or strong inducers of CYP3A4/5
Medications with a low therapeutic index that are primarily metabolized by CYP3A4/5, CYP2C8 and/or CYP2C9.
Medications with a known risk of prolonging the QT interval or inducing Torsades de
Pointes.
12. Patient is currently receiving treatment with warfarin sodium (Coumadin®) or any other
coumarin-derivative anticoagulants.
13. Patient is receiving unstable or increasing doses of corticosteroids. If patients are on
corticosteroids for endocrine deficiencies or tumor-associated symptoms (non-CNS), dose
must have been stabilized (or decreasing) for at least 5 days before first dose of study
treatment.
14. Patient is receiving treatment with any enzyme-inducing anticonvulsant (Appendix 1) that cannot be discontinued at least 1 week before first dose of study treatment, and for the
duration of the study. Patient on non enzyme-inducing anticonvulsants is eligible.
15. Patient is pregnant or nursing (lactating) woman, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
16. . Patient is a woman of child-bearing potential, defined as a woman physiologically capable of becoming pregnant, unless she is using highly effective contraception during the study and for 3 months after stopping treatment. Highly effective contraception is defined as any of:
Total abstinence: when this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception].
Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In
case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment .
Male partner sterilization (at least 6 months prior to screening). (With the appropriate
post-vasectomy documentation of the absence of sperm in the ejaculate). [For female
subjects on the study the vasectomized male partner should be the sole partner for that
patient].
Use of a combination of any two of the following (a+b or a+c or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormonal vaginal ring or transdermal hormone contraception.
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
In case of use of oral contraception, women should have been stable on the same pill for a
minimum of 3 months before taking study treatment .
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to screening. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
17. Sexually active males unless they use a condom during intercourse while taking the drug
and for 3 months after the last dose of study treatment. Male patients should not father a
child for 3 months after the last dose of study treatment. A condom is required to be used
also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
18. Patient has other severe, acute, or chronic medical or psychiatric conditions or laboratory abnormalities that in the opinion of the investigator may increase the risk associated with study participation, or that may interfere with the interpretation of study results.
1. Patient with known hypersensitivity to any of the excipients of LDK378 (microcrystalline
cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate)
2. Patient with a history of severe hypersensitivity reaction to platinum containing drugs,
pemetrexed or any known excipients of these drugs.
3. Patient has received previous systemic anticancer therapy (e.g. cytotoxic drugs, monoclonal antibody therapy, crizotinib or other ALK inhibitors, or other targeted therapies, either experimental or not) for newly diagnosed stage IIIB or IV NSCLC or relapsed locally advanced or metastatic NSCLC with exception of neo-adjuvant or adjuvant therapy as depicted in inclusion criteria 6.
4. Patient with symptomatic CNS metastases who is neurologically unstable or has required
increasing doses of steroids within the 2 weeks prior to screening to manage CNS symptoms.
5. Patient has history of carcinomatous meningitis
6. Patient has received radiotherapy ≤ 2 weeks prior to starting the study treatment or has not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study treatment is allowed.
7.Patient has had major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within
4 weeks prior (2 weeks for resection of brain metastases) to starting study treatment or has
not recovered from side effects of such procedure. Video-assisted thoracic surgery (VATS) and mediastinoscopy will not be counted as major surgery and patients can receive study treatment ≥1 week after the procedure.
8. Patient with a concurrent malignancy or history of a malignant disease other than NSCLC
that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this
exclusion include the following: completely resected basal cell and squamous cell skin
cancers, and completely resected carcinoma in situ of any type.
9. Patient has clinically significant, uncontrolled heart disease and/or recent cardiac event
(within 6 months), such as:
Unstable angina within 6 months prior to screening
Myocardial infarction within 6 months prior to screening
History of documented congestive heart failure (New York Heart Association functional classification III-IV)
Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without antihypertensive medication. Initiation or adjustment of antihypertensive medication (s) is allowed prior to screening .
Ventricular arrhythmias.
Supraventricular and nodal arrhythmias not controlled with medication.
Other cardiac arrhythmia not controlled with medication.
Corrected QT (QTcF) > 470 ms using Fridericia’s correction on the screening ECG (as mean of triplicate ECGs)
10. Patient has impairment of GI function or GI disease that may significantly alter the
absorption of LDK378 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea,
or malabsorption syndrome).
11. Patient receiving treatment with medications that meet one of the following criteria and
that cannot be discontinued at least 1 week prior to the start of treatment with LDK378
and for the duration of the study:
Strong inhibitors or strong inducers of CYP3A4/5
Medications with a low therapeutic index that are primarily metabolized by CYP3A4/5, CYP2C8 and/or CYP2C9.
Medications with a known risk of prolonging the QT interval or inducing Torsades de
Pointes.
12. Patient is currently receiving treatment with warfarin sodium (Coumadin®) or any other
coumarin-derivative anticoagulants.
13. Patient is receiving unstable or increasing doses of corticosteroids. If patients are on
corticosteroids for endocrine deficiencies or tumor-associated symptoms (non-CNS), dose
must have been stabilized (or decreasing) for at least 5 days before first dose of study
treatment.
14. Patient is receiving treatment with any enzyme-inducing anticonvulsant (Appendix 1) that cannot be discontinued at least 1 week before first dose of study treatment, and for the
duration of the study. Patient on non enzyme-inducing anticonvulsants is eligible.
15. Patient is pregnant or nursing (lactating) woman, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
16. . Patient is a woman of child-bearing potential, defined as a woman physiologically capable of becoming pregnant, unless she is using highly effective contraception during the study and for 3 months after stopping treatment. Highly effective contraception is defined as any of:
Total abstinence: when this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception].
Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In
case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment .
Male partner sterilization (at least 6 months prior to screening). (With the appropriate
post-vasectomy documentation of the absence of sperm in the ejaculate). [For female
subjects on the study the vasectomized male partner should be the sole partner for that
patient].
Use of a combination of any two of the following (a+b or a+c or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormonal vaginal ring or transdermal hormone contraception.
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
In case of use of oral contraception, women should have been stable on the same pill for a
minimum of 3 months before taking study treatment .
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to screening. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
17. Sexually active males unless they use a condom during intercourse while taking the drug
and for 3 months after the last dose of study treatment. Male patients should not father a
child for 3 months after the last dose of study treatment. A condom is required to be used
also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
18. Patient has other severe, acute, or chronic medical or psychiatric conditions or laboratory abnormalities that in the opinion of the investigator may increase the risk associated with study participation, or that may interfere with the interpretation of study results.
The Estimated Number of Participants
-
Taiwan
34 participants
-
Global
376 participants
